The present invention relates to a method and medicament for pharmacological treatment of accidental extravasation of topoisomerase II poisons such as anthracyclines.
In particular, the invention relates to the systemic as well as the local administration of a topo II inhibitor such as the bisdioxopiperazine ICRF-187 in the treatment of accidental extravasation of a topoisomerase II poison such as the anthracyclines daunorubicin, doxorubicin, epirubicin, or idarubicin.
Topoisomerase II, topoisomerase II poisons, and topoisomerase II catalytic Inhibitors
The topoisomerase II (topo II) enzymes belong to a system of nuclear enzymes involved in the processing of DNA during the cell cycles. In short, they are able to introduce transient cleavage of both strands of the DNA double helix, thereby allowing the passage of another intact DNA double strand through the cleavage. The cleavage time is very short. Drugs acting on topo II are divided into two main categories, topo II poisons and topo II catalytic inhibitors.
The topo II poisons shift the equilibrium of the catalytic cycle towards cleavage, thereby increasing the concentration of the transient protein-associated breaks in the genome (1) (see FIG. 1). That is, they trap the cleavable complexes, which converts the essential topo II enzyme into a lethal one (2).
The topo II catalytic inhibitor is an entirely different group of drugs. They act by interfering with the overall catalytic function, which can be accomplished in at least two ways. One is the inhibition of the initial binding of topo II to DNA as in the case of chloroquine (3) and aclarubicin (4,5). The other is by locking topo II in its closed-clamp step after religation as appears to be the case for the ICRF-187 and its analogues (6-9).
Anthracyclines
The anthracyclines comprise a group of widely used cytotoxic compounds with activity in numerous malignant diseases.
Daunorubicin, the first anthracycline antibiotic to be discovered in the early 1960""s, was isolated from streptomyces cultures. Soon hereafter, doxorubicin was extracted and investigated clinically. The two drugs have a wide range of activity against malignant diseasesxe2x80x94daunorubicin primarily in the field of haematological malignancies and doxorubicin against solid tumors. Epirubicin is a stereoisomer of doxorubicin with the same indications as but slightly lesser potency and less cardiac toxicity than the parent drug. Idarubicin (4-demethoxydaunorubicin) resembles daunorubicin but lacks a methoxyl group at the C-4 position. It is more lipophilic than the other anthracycline compounds and penetrates the blood-brain barrier more readily.
The mechanism of action of these drugs is not well understood. The antitumor effect is explained by the ability to inhibit the nuclear enzyme DNA topo II. Thus, the anthracyclines are classified as topo II poisons. However, the drugs also interact with other enzymes, e.g. topo I, DNA- and RNA polymerases, and helicases. Furthermore, they are able to intercalate with DNA, a process that may initiate free radical damage. During the intracellular metabolism of the anthracycline, the anthraquinone nucleus is converted to a free radical semiquinone intermediate that might exert local DNA destruction. Moreover, the anthracyclines are capable of chelating iron and forming ternary complexes with DNA. However, the drug concentration required to induce free radical DNA damage is higher than the achievable clinical concentrations. Thus, this mechanism appears to be less important in regard to antitumor effect.
The most pronounced side effects of anthracycline therapy are cardiotoxicity (10,11), hematological toxicity, gastointestinal toxicity, and the extremely severe local toxicity following accidental extravasation (see below).
ICRF-187
The bisdioxopiperazine ICRF-187 (dexrazoxane) is the water-soluble (+) enantiomer of razoxane (ICRF-159). It is a highly specific topo II catalytic inhibitor. A hypothesis has been that ICRF-187, as an analogue of the cation binder EDTA, protects against free radical damage by binding and thus concealing iron from oxygen (12). However, we have recently demonstrated that cells with acquired resistance to ICRF-187 carry mutations in topo II (a subtype of topo II) which are in different sites than those induced by topo II poisons such as daunorubicin and etoposide. We confirmed that these mutations were functional using humanised topo II in yeast (13, 14). Accordingly, our assumptions were correct when we suggested that ICRF-187 was a specific topo II agent. We have demonstrated that it is possible to abolish the cell kill caused by etoposide, daunorubicin, and idarubicin at 2 different steps (See also FIG. 2) in the enzyme""s catalytic cycle. Thus, intercalating drugs as chloroquine inhibit the enzyme from reaching its target (3,15,16) and the bisdioxopiperazine ICRF-187 locks the enzyme at a closed clamp step (4,17,18).
ICRF-187 is registrated as a cardioprotective agent (Zinecard(copyright), Cardioxane(copyright)) against anthracycline induced cardiotoxicity.
Extravasation of Anthracyclines
Accidental extravasation has been estimated to occur in 0.6 to 6% of all patients receiving chemotherapy. Chemotherapeutic agents such as the anthracyclines which bind to DNA are especially prone to cause severe tissue damage on extravasation. The tissue injury may not appear for several days or even weeks and may continue to worsen for months, probably due to drug recycling into adjacent tissue. The local toxicity is characterized by acute pain, erythema, and swelling at the extravasation site and it often progresses to ulceration. Indeed, it has been demonstrated that the anthracyclines, e.g. doxorubicin, can persist in the tissue for at least a month (20). While small ulcerations may on occasion heal, large ulcerations require surgical excision for relief of pain and salvage of underlying tissue. An early surgical approach with extensive debridement of the involved area followed by skin grafting is therefore the treatment of choice (21).
During the last two decades a number of possible treatment modalities have been investigated.
Local cooling with ice lasting from 1 hour to 3 days or longer is a widely used treatment (22), that should be initiated immediately. The use of local injection or topical administration of corticosteroids as an anti-inflammatory treatment has produced contradictory results in animal and human studies (23). Inflammation does not seem to be a part of the pathophysiology and corticosteroids may even worsen the lesions. The effect of local sodium bicarbonate (24) has been investigated in experiments with varying results as have local sodium thiosulphate, hyaluronidase (25), and beta-adrenergics (agonists and antagonists) (26). Experimental treatment and clinical use of topical dimethyl sulfoxide (DMSO) for 2 to 7 days with or without xcex1-tocoferol (vitamin E) (27-29) has indicated beneficial effect in both animal and in uncontrolled clinical studies, at least of DMSO. The results are however not uniform. In one study intraperitoneal (IP) as well as topical treatment with xcex1-tocoferol, Ginkgo biloba extract, or pentoxifylline of intradermal (ID) doxorubicin in rats decreased the tissue level of malondialdehyde, thus suggestive of scavenge of free radicals (29). Bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3) can react with doxorubicin in vitro to produce an inactive metabolite deoxy-doxorubicin aglycone, and intralesional treatment with DHM3 of ID doxorubicin extravasation in a swine has shown some benefit (30). No confirmative studies have though been published since 1988.
In the almost all animal studies anthracycline has been injected intradermally. It has been argued, that injections beneath the rodent skin muscle layer, panniculus carnosus, tend to cause irregular ulcerative lesions, whereas intradermal injection produces uniform skin necrosis and ulceration (32). However, ID injection of anthracyclines has also been the investigated methods in swine models.
Frozen-section fluorescence of doxorubicin and epirubicin extravasation has been claimed to be an efficient method of detection of residual drug in the tissue, that could serve as a guide to surgical treatment of infiltration (31,33).
The histological changes have been studied in a rabbit model, where the earliest changes included vascular obliteration and necrobiosis of collagen. At no point were inflammatory cells found to play a primary role (34). Small vesicles of unknown etiology have been seen in the necrotic dermis of rats (32). No studies have yet investigated apoptosis.
No studies mentioning neither ICRF-187 nor other bisdioxopiperazines nor topo II catalytic inhibitors as a treatment option have been published. Moreover, none of the published studies or reviews has discussed the topo II enzymes as a potential target for an antidote to extravasation of anthracyclines or other topo II poisons. Finally, the vast majority of animal experiments have dealt with local treatment of intradermally extravasated anthracyclines. It is our opinion that subcutaneous administration best resembles the clinical reality. Furthermore, as demonstrated in the examples, the wound area x time (the area under the curve, AUC) is a very reproducible parameter.
The issue of local versus systemic treatment is very important, as use of central venous access devices increases. When multiple infusions are anticipated over a prolonged period, placement of subcutaneous reservoirs with long indwelling lines should be considered. This is often the case in anthracycline therapy. The placement of short-term and long-term indwelling central venous catheters has now become a common surgical procedure performed on cancer patients. However, such devices are not free form leakage, displacement problems, or infectious thrombi. An extravasation incidence of 6.4 percent has been reported (35). Obviously it is difficult to treat local extravasation from centrally located indwelling devices. In such a situation a systemic treatment is far more suitable, but has until now not been available.